 | |
| Clinical data | |
|---|---|
| Other names | NAP; Naphthylisopropylamine; NIPA; PAL-287; Naphetamine; Amnetamine; 1-(2-Naphthyl)-2-aminopropane; beta-Methylnapthylethylamine; β-Methylnaphthylethylamine; 1-(β-Naphthyl)-2-aminopropane |
| Routes of administration | Oral |
| ATC code |
|
| Legal status | |
| Legal status |
|
| Identifiers | |
| |
| CAS Number | |
| PubChemCID | |
| ChemSpider | |
| UNII | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C13H15N |
| Molar mass | 185.270 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Naphthylaminopropane (NAP; code namePAL-287), also known asnaphthylisopropylamine (NIPA), is anexperimentaldrug of theamphetamine andnaphthylaminopropane families that was under investigation for the treatment ofalcohol andstimulantaddiction.[1][2]
Naphthylaminopropane is aserotonin–norepinephrine–dopamine releasing agent (SNDRA).[3][4] ItsEC50Tooltip half-maximal effective concentration values for induction ofmonoamine release are 3.4 nM forserotonin, 11.1 nM fornorepinephrine, and 12.6 nM fordopamine.[3][4]
The drug is also anagonist of theserotonin5-HT2A,5-HT2B, and5-HT2C receptors.[2] ItsEC50 values are 466 nM at the serotonin 5-HT2A receptor, 40 nM at the serotonin 5-HT2B receptor, and 2.3 nM at the serotonin 5-HT2C receptor.[2] It is afull agonist of the serotonin 5-HT2A and 5-HT2B receptors and a weakpartial agonist of the serotonin 5-HT2C receptor (EmaxTooltip maximal efficacy = 20%).[1][2]
Naphthylaminopropane has been found to act as a potentmonoamine oxidase A (MAO-A)inhibitor, with anIC50Tooltip half-maximal inhibitory concentration of 420 nM.[5][6] This is similar to the potency of the well-known MAO-A inhibitorspara-methoxyamphetamine (PMA) and4-methylthioamphetamine (4-MTA).[5]
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Ref |
|---|---|---|---|---|
| d-Amphetamine | 6.6–10.2 | 5.8–24.8 | 698–1,765 | [7][8][9][10][11] |
| Naphthylaminopropane (NAP; PAL-287) | 11.1 | 12.6 | 3.4 | [4][9] |
| d-Methamphetamine | 12.3–14.3 | 8.5–40.4 | 736–1,292 | [7][12][9][11] |
| Methylnaphthylaminopropane (MNAP; PAL-1046) | 34 | 10 | 13 | [13][14] |
| l-Methcathinone | 13.1 | 14.8 | 1,772 | [15][10] |
| 2-Naphthylmethcathinone (BMAPN; βk-MNAP) | 94% at 10 μM | 34 | 27 | [16][17] |
| d-Ethylamphetamine | 28.8 | 44.1 | 333.0 | [18][19] |
| Ethylnaphthylaminopropane (ENAP; PAL-1045) | 137 | 46a | 12a | [13] |
| Phenmetrazine | 29–50.4 | 70–131 | 7,765–>10,000 | [20][9][21][22] |
| Naphthylmetrazine (PAL-704) | 203 | 111 | RI (105) | [22] |
| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. Theassays were done in rat brainsynaptosomes and humanpotencies may be different. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds.Footnotes:aENAPTooltip Ethylnaphthylaminopropane is apartial releaser of serotonin (EmaxTooltip maximal efficacy = 66%) and dopamine (Emax = 78%).Refs:[23][24] | ||||
Inanimal studies, naphthylaminopropane was shown to reducecocaineself-administration, yet produced relatively weakstimulant effects when administered alone, being a much less effective stimulant thandextroamphetamine.[4][25][26] Further research was being conducted in primates to see if the drug would be a useful substitute for treatingdrug addiction in humans.[27]
An important observation is that in behavioral studies, rodents would consistentlyself-administerselectivenorepinephrine–dopamine releasing agents (NDRAs) like dextroamphetamine, yet compounds that alsopotently releaseserotonin like naphthylaminopropane would not be self-administered.[4] In addition to the drug's effects on self-administration, the available evidence suggests that thelocomotor activation caused by dopamine releasers is also dampened when they additionally induce serotonin release.[24] Notably, despite potent dopamine release induction, naphthylaminopropane produces weak or no locomotor activation in rodents.[1]
The highaffinity of naphthylaminopropane for the serotonin 5-HT2C receptor meant that it might function as anappetite suppressant and was being considered for possible clinical use for this indication (i.e.,weight loss). However, concerns were raised over the affinity of the drug for the serotonin 5-HT2B receptor, since some of the more serious side effects of the serotonin-releasingweight loss drugfenfluramine were linked to activation of this receptor.[28] It is uncertain, although was considered unlikely per the researchers who developed the drug, that activation of the serotonin 5-HT2A and 5-HT2B receptors occurs to a significant degreein vivo.[1]
Naphthylaminopropane was first described in thescientific literature by 1939.[29][25] The drug is also known as 2-naphthylaminopropane (2-NAP) or β-naphthylaminopropane, and it was described along with itspositional isomer1-naphthylaminopropane (1-NAP; α-naphthylaminopropane).[26][25] Both 2-NAP and 1-NAP failed to substitute fordextroamphetamine in rodentdrug discrimination tests, suggesting that they lackpsychostimulant-like effects.[26] The β-keto andN-methylanalogue of 2-NAP has been assessed and was found to act as a potent SNDRA similarly to naphthylaminopropane.[16]
Naphthylaminopropane isstructurally related to certain rigid analogues ofamphetamine.[26] Rigid amphetamine analogues include2-aminotetralin (2-AT),2-amino-1,2-dihydronaphthalene (2-ADN),1-phenylpiperazine (1-PP),2-aminoindane (2-AI),6-ABTooltip 6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene, and7-ABTooltip 7-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene.[26][30][31]
A fewderivatives of naphthylaminopropane have been developed or have appeared, includingmethamnetamine (N-methylnaphthylaminopropane; MNAP; PAL-1046),N-ethylnaphthylaminopropane (ENAP; PAL-1045), andBMAPN (βk-methamnetamine; β-keto-MNAP; 2-naphthylmethcathinone).[13][14][16][32] Like naphthylaminopropane, these derivatives also act as potentmonoamine releasing agents, including of serotonin, norepinephrine, and/or dopamine.[13][14][16][32]
RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays.
FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]
